The SBIR proposal addresses a critical national need for therapies to treat complications from smallpox vaccination. Vaccination against smallpox is accompanied with numerous adverse reactions, some of which have high fatality rates. Ironically, it was the eradication of smallpox, which the WHO declared complete worldwide in 1979, and the cessation of routine immunizations against smallpox that has left the majority of Americans alive today susceptible to the disease and hence vulnerable to a bioterrorist smallpox attack. The only known treatment for complications from smallpox vaccination is subsequent inoculation with antibody against vaccinia virus, the immunogen in the vaccine (VIG). National stores of this reagent, which is isolated from the blood of vacinees, is in short supply, and in the absence of a smallpox immunization program, is difficult to replenish. This proposal is to develop a large animal system for producing human polyclonal antibody against vaccinia virus, It has been shown that trangenic mice carrying an artificial human chromosome (HAC) produce human polycolonal antibody of all classes and with a broad repertoire when challenged with antigen. In the current work, a similar strategy would be applied to cattle, where the yield of antibody would be far greater than with mice. We have already shown that we can create cattle clones that have a HAC containing the human Ig genes, and that the chromosome is stable and is expressed throughout fetal development into neonatal life. Further work is proposed to characterize the immune response to vaccinia virus in normal and in cloned calves. This novel and practical solution to the limited supply of human VIG has several advantages. First, it would enable the production of large quantities of human antibody at a reasonable cost. Second, it would provide greater flexibility in designing immunization strategies for producing high titer, high specificity antibody beyond what is possible with human volunteers. Third, it would provide a new enabling technology for producing clinically important human antibody reagents against other bacterial and viral pathogens.